19-49061795-C-T

Variant names:

• chr19-49061795-C-T
• rs200786116
• NM_006179.5:c.203G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006179.5(NTF4):​c.203G>A​(p.Arg68Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000641 in 1,556,614 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: NTF4 NM_006179.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.10

Genes affected

NTF4 (HGNC:8024): (neurotrophin 4) This gene is a member of a family of neurotrophic factors, neurotrophins, that control survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and less influenced by environmental signals. While knock-outs of other neurotrophins including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 prove lethal during early postnatal development, NTF5-deficient mice only show minor cellular deficits and develop normally to adulthood. [provided by RefSeq, Jul 2008]

ENSG00000283663 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056933165).
• BP6: Variant 19-49061795-C-T is Benign according to our data. Variant chr19-49061795-C-T is described in ClinVar as [Benign]. Clinvar id is 783846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 493 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTF4	NM_006179.5	c.203G>A	p.Arg68Gln	missense_variant	Exon 2 of 2	ENST00000593537.2	NP_006170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTF4	ENST00000593537.2	c.203G>A	p.Arg68Gln	missense_variant	Exon 2 of 2	6	NM_006179.5	ENSP00000469455.1
ENSG00000283663	ENST00000599795.5	n.203G>A		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000470689.1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000596 AC: 93 AN: 156056 Hom.: 0 AF XY: 0.000475 AC XY: 40 AN XY: 84190

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000360 AC: 505 AN: 1404300 Hom.: 3 Cov.: 32 AF XY: 0.000284 AC XY: 197 AN XY: 693696

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.000331

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000361

Gnomad4 SAS exome AF: 0.0000498

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000790

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00311 AC XY: 232 AN XY: 74482

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.00386

ESP6500AA AF: 0.00865 AC: 35

ESP6500EA AF: 0.000249 AC: 2

ExAC AF: 0.000494 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NTF4-related disorder Benign:1

Apr 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.63	T;.
Polyphen		0.0	B;.
Vest4		0.20
MVP		0.60
ClinPred		0.0098	T
GERP RS		2.9
Varity_R		0.053
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200786116; hg19: chr19-49565052; COSMIC: COSV104619270; COSMIC: COSV104619270;